1. San Antonio Breast Cancer Symposium, December 5-9, 2017
Pooled analysis of five randomized trials investigating temporary ovarian suppression with gonadotropin-releasing hormone analogs during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal early breast cancer patients
Matteo Lambertini1, Halle C.F. Moore2, Robert C.F. Leonard3, Sibylle Loibl4, Pamela Munster5, Marco Bruzzone6, Luca Boni7, Joseph M. Unger8, Richard A. Anderson9, Keyur Mehta4, Susan Minton10, Francesca Poggio6, Kathy S. Albain11, Douglas J.A. Adamson12, Bernd Gerber13, Amy Cripps14, Gianfilippo Bertelli15, Sabine Seiler4, Marcello Ceppi6, Ann H. Partridge16, and Lucia Del Mastro6
1Institut Jules Bordet and Université Libre de Bruxelles (U.L.B.), Brussels, Belgium. 2Cleveland Clinic Foundation, Taussig Cancer Institute, Cleveland, OH. 3Imperial College, London, UK. 4GBG - German Breast Group, Neu-Isenburg, Germany. 5UCSF - University of California, San Francisco, CA. 6Ospedale Policlinico San Martino-IST, Genova, Italy. 7AOU Careggi and Istituto Toscano Tumori, Firenze, Italy. 8SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA. 9MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK. 10Moffitt Cancer Center, Tampa, FL. 11Loyola University Medical Center, Cardinal Bernardin Cancer Center, Maywood, IL. 12Tayside Cancer Centre, Ninewells Hospital, Dundee, UK. 13University Hospital Rostock, Rostock, Germany. 14Nexgen Oncology, Dallas, TX. 15Singleton Hospital, Swansea, UK. 16Dana-Farber Cancer Institute, Boston, MA.
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2. San Antonio Breast Cancer Symposium, December 5-9, 2017
Disclosures
Lambertini Matteo:
Consultant or advisor: Teva
Travel grant: Astellas
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3. for young women with breast cancer”
San Antonio Breast Cancer Symposium, December 5-9, 2017
Background
“Fertility preservation and pregnancy-related issues are high priority areas of concern
for young women with breast cancer”
Paluch-Shimon S et al, Breast 2017;35:203-17
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4. San Antonio Breast Cancer Symposium, December 5-9, 2017
Background
Premature ovarian insufficiency (POI) is a common side effect of chemotherapy in premenopausal patients with substantial negative impact on their quality of life
Oocyte/embryo cryopreservation are standard strategies for fertility preservation but they do not prevent the risk of chemotherapy-induced POI
Temporary ovarian suppression with GnRHa during chemotherapy has been studied in several RCTs as a strategy to preserve ovarian function and potential fertility
However, data are mixed and its role remains controversial
Paluch-Shimon S et al, Breast 2017;35: Loren AW et al, J Clin Oncol 2013;31: Peccatori F et al, Ann Oncol 2013;24 Suppl 6;vi Lambertini M et al, Ann Oncol 2015;26: Lambertini M et al, Eur J Cancer 2017;71:25-33.
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5. Study Objectives and Endpoints
San Antonio Breast Cancer Symposium, December 5-9, 2017
Study Objectives and Endpoints
Systematic review and meta-analysis of individual patient data from RCTs to evaluate the efficacy (ovarian function and fertility preservation) and the safety (survival outcomes) of GnRHa use during chemotherapy
Primary endpoints
POI rate (according to the definition used as primary endpoint in each trial)
Post-treatment pregnancy rate
Secondary endpoints
Amenorrhea rates one year and two years after the end of chemotherapy
Disease-free survival (DFS) and overall survival (OS)
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6. Study Characteristics Anglo Celtic Group OPTION6
San Antonio Breast Cancer Symposium, December 5-9, 2017
Study Characteristics
PROMISE-GIM61,2
POEMS/SWOG S02303
Moffitt-led trial4
GBG-37 ZORO5
Anglo Celtic Group OPTION6
Definition of POI
No resumption of menstrual activity and postmenopausal levels of FSH and E2
Amenorrhea for the prior 6 months and postmenopausal levels of FSH
No maintenance of menses and no resumption of menses
No re-appearance of two consecutive menstrual periods within 21 to 35 days
Amenorrhea with elevated FSH
Timing of POI after chemotherapy
12 months
24 months
6 months
Between 12 and 24 months
Sample size
281
257 48 60
227
ER status for eligibility
ER-positive and ER-negative
ER-negative only
Upper age limit for eligibility
≤ 45 years
≤ 49 years
≤ 44 years
None
Type of GnRHa
Triptorelin
Goserelin
1. Del Mastro L et al, JAMA 2011;306: Lambertini M et al, JAMA 2015;314: Moore HCF et al, N Engl J Med 2015;372:
4. Munster P et al, J Clin Oncol 2012;30: Gerber B et al, J Clin Oncol 2011;29: Leonard RCF et al, Ann Oncol 2017;28:
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7. Baseline Characteristics
San Antonio Breast Cancer Symposium, December 5-9, 2017
Baseline Characteristics
GnRHa group
(n=436)
No. (%)
Control group
(n=437)
p value*
Age, median (interquartile range), years
38 (34-42)
39 (35-42)
0.258
Age distribution, years
≤ 40
≥ 41
297 (68.1)
139 (31.9)
283 (64.8)
154 (35.2)
0.316
Estrogen receptor status
Positive
Negative
Missing
177 (40.6)
257 (58.9)
2 (0.5)
173 (39.6)
262 (59.9)
0.782
Type of chemotherapy
Anthracycline only-based
Anthracycline- and taxane-based
Non anthracycline-based
194 (44.5)
227 (52.1)
6 (1.4)
9 (2.1)
198 (45.3)
210 (48.0)
13 (3.0)
16 (3.7)
0.196
Cumulative cyclophosphamide dose, median (interquartile range), mg/m2
4000 ( )
3960 ( )
0.585
*Calculated by excluding missing data
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8. Premature-Ovarian Insufficiency Rate
San Antonio Breast Cancer Symposium, December 5-9, 2017
Premature-Ovarian Insufficiency Rate
OR* 0.38 (95% CI )
p<0.001
Subgroup analysis
14.1%
30.9%
GnRHa group
n=363
Control group
n=359
*Odds ratio (OR) adjusted for age, estrogen receptor status, type and duration of chemotherapy administered
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9. San Antonio Breast Cancer Symposium, December 5-9, 2017
Amenorrhea Rates
One-Year Amenorrhea
Two-Year Amenorrhea
OR* 0.92 (95% CI ); p=0.623
OR* 0.51 (95% CI ); p=0.009
36.8%
40.4%
18.2%
30.0%
GnRHa group
n=386
Control group
n=374
GnRHa group
n=214
Control group
n=210
*Odds ratio (OR) adjusted for age, estrogen receptor status, type and duration of chemotherapy administered
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10. Post-Treatment Pregnancy Rate
San Antonio Breast Cancer Symposium, December 5-9, 2017
Post-Treatment Pregnancy Rate
GnRHa group
(n = 37)
No. (%)
Control group
(n = 20)
Age distribution, years
≤ 40
≥ 41
37 (100)
0 (0.0)
20 (100)
Estrogen receptor status
Positive
Negative
6 (16.2)
31 (83.8)
2 (10.0)
18 (90.0)
GnRHa Group: 37/359 (10.3%)
vs.
Control Group: 20/367 (5.5%)
IRR* 1.83 (95% CI )
p=0.030
*Incidence rate ratio (IRR)
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11. Disease-free survival
San Antonio Breast Cancer Symposium, December 5-9, 2017
Survival Outcomes
Disease-free survival
Overall survival
HR* 1.01 (95% CI )
p=0.999
HR* 0.67 (95% CI )
p=0.083
*Hazard ratio (HR) adjusted for age, estrogen receptor status, type and duration of chemotherapy administered and tumor stage
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12. San Antonio Breast Cancer Symposium, December 5-9, 2017
Conclusions
Administration of GnRHa during chemotherapy was associated with a significant reduction in the risk of chemotherapy-induced POI
A greater number of women in the GnRHa group had a post-treatment pregnancy
Similar DFS and OS were observed between groups irrespective of the estrogen receptor status of the disease
This strategy should be considered as an option to reduce the likelihood of chemotherapy-induced POI and potentially improve future fertility in premenopausal early breast cancer patients undergoing (neo)adjuvant chemotherapy
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13. San Antonio Breast Cancer Symposium, December 5-9, 2017
Acknowledgments
All the patients enrolled in the trials and their families
All the investigators and research teams
The Gruppo Italiano Mammella (GIM) study group, the SWOG, the Anglo Celtic Group and the German Breast Group
Italian Association for Cancer Research (AIRC) for supplemental funding
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14. San Antonio Breast Cancer Symposium, December 5-9, 2017
Acknowledgments
European Society for Medical Oncology (ESMO) for a Translational Research Fellowship at Institut Jules Bordet (Brussels, Belgium)
San Antonio Breast Cancer Symposium (SABCS) Scientific Committee for a SABCS Clinical Scholar Award
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